Clinical pharmacology and tolerability of REC-994, a redox-cycling nitroxide compound, in randomized phase 1 dose-finding studies.

Publisher: John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 101626369 Publication Model: Print Cited Medium: Internet ISSN: 2052-1707 (Electronic) Linking ISSN: 20521707 NLM ISO Abbreviation: Pharmacol Res Perspect Subsets: MEDLINE

Original Publication: [Hoboken, NJ] : John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics, [2013]-

Cyclic N-Oxides*/administration & dosage ; Cyclic N-Oxides*/pharmacokinetics ; Cyclic N-Oxides*/adverse effects ; Dose-Response Relationship, Drug* ; Spin Labels*; Humans ; Adult ; Male ; Female ; Young Adult ; Middle Aged ; Adolescent ; Double-Blind Method ; Healthy Volunteers ; Oxidation-Reduction ; Administration, Oral ; Hemangioma, Cavernous, Central Nervous System/drug therapy

Cerebral cavernous malformation (CCM) has variable clinical symptoms, including potentially fatal hemorrhagic stroke. Treatment options are very limited, presenting a large unmet need. REC-994 (also known as tempol), identified as a potential treatment through an unbiased drug discovery platform, is hypothesized to treat CCMs through a reduction in superoxide, a reactive oxygen species. We investigated the safety, tolerability, and pharmacokinetic profile of REC-994 in healthy volunteers. Single- and multiple-ascending dose (SAD and MAD, respectively) studies were conducted in adult volunteers (ages 18-55). SAD study participants received an oral dose of REC-994 or placebo. MAD study participants were randomized 3:1 to oral doses of REC-994 or matching placebo, once daily for 10 days. Thirty-two healthy volunteers participated in the SAD study and 52 in the MAD study. Systemic exposure increased in proportion to REC-994 dose after single doses of 50-800 mg and after 10 days of dosing over the 16-fold dose range of 50-800 mg. Median T max and mean t 1/2 were independent of dose in both studies, and the solution formulation was more rapidly absorbed. REC-994 was well tolerated. Treatment-emergent adverse effects across both studies were mild and transient and resolved by the end of the study. REC-994 has a favorable safety profile and was well tolerated in single and multiple doses up to 800 mg with no dose-limiting adverse effects identified. Data support conducting a phase 2 clinical trial in patients with symptomatic CCM.
(© 2024 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

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Recursion Pharmaceuticals, Inc.

Keywords: antioxidants; genetic diseases; oxidative stress; pharmacokinetics; phase 1

0 (Cyclic N-Oxides)
U78ZX2F65X (tempol)
0 (Spin Labels)

Date Created: 20240424 Date Completed: 20240424 Latest Revision: 20240508

20250114

PMC11040693

10.1002/prp2.1200

38655895